Activation of brain cells by receptor activation or changes in ion flux can result in the rapid and transient expression of certain key genes, such as the c-fos gene, which are capable of controlling and orchestrating the transcription of a large number of dependent genes. Such altered gene expression may underlie normal, as well as pathophysiological, long term changes in cell function. We have mapped the expression of the c-fos gene in rat brain during alcohol intoxication and withdrawal and have identified several brain structures in which expression is increased during alcohol withdrawal. We have demonstrated that the regional expression of c-fos mRNA observed during alcohol withdrawal can be mimicked by acute administration of N-methyl-D-aspartic acid (NMDA) and stereospecifically blocked by the NMDA receptor/ionophore blocker, MK-801. We have also demonstrated that levels of glutamate (an endogenous ligand for NMDA receptors), but not other excitatory and inhibitory amino acid putative neurotransmitters, are increased in the brain during alcohol withdrawal. Current research is focused on pharmacologically characterizing the increased expression of c-fos mRNA observed during alcohol withdrawal. In addition we are developing and screening DNA probes for other second messenger-dependent genes which may exhibit altered expression during alcohol intoxication or withdrawal.